The goals of this project are to determine if the expression of the hepatitis C virus (HCV) core protein alters the ability of the immune system to cause hepatitis, and results in immune dysfunctions by altering the ability of the immune system to generate effectors. The first aim is to determine if expression of the core protein in hepatocytes alters their ability to be recognized by CD8+ and CD4+ immune effectors. This will be accomplished by adoptive transfer of NS5-specific immune effectors into transgenic (TG) mice expressing both NS5 and core protein under the control of a hepatocyte-specific promoter. These mice will be compared to mice expressing the NS5 gene only in hepatocytes. The second aim is based on Dr. Lai's data (Project I) showing the interaction(s) of the core protein with members of the tumor necrosis factor receptor family. TG mice expressing the core protein under control of the CMV promoter will be examined for immune defects related to alterations in receptor signaling. The hypothesis of the final aim is based on the findings that HCV infects both PBMC and bone marrow cells. Our hypothesis is that expression of the core protein in either macrophage antigen presenting cells or the T cells themselves leads to immune dysregulation. This ability to alter immune responsiveness facilitates HCV persistence. Tests of this aim hypothesis will initially use bone marrow chimeras to determine if expression of the core protein alters immune responsiveness. It will be pursued by specific expression of the core protein in either macrophages or in T cells using cell type specific promoters. This project will establish a small animal model system for studying the pathogenesis of HCV, which is one of the major goals of this center. This project interacts closely with Project I.